Antiphospholipid syndrome is an acquired multisystem
disorder characterized by recurrent thromboses in the arterial system, venous
system, or both. Antiphospholipid syndrome is classified into 2 groups: primary
and secondary. Secondary antiphospholipid syndrome is often associated with
systemic lupus erythematosus and less frequently with infections, drugs and
other diseases. Serologic markers are antiphospholipid antibodies, lupus anticoagulant
and anticardiolipin. The primary diagnostic criteria include arterial thrombosis
or venous thrombosis and recurrent fetal loss. About 41% of patients with lupus
anticoagulant have skin lesions as the first sign of antiphospholipid syndrome.
Cutaneous manifestations include livedo reticularis, cutaneous ulceration and
livedo vasculitis. The mainstays of prophylaxis and treatment of thrombosis
are anticoagulant and antiplatelet agents.

Keywords: Skin manifestations; Antiphospholipid
syndrome; Thrombosis

INTRODUCTION

Antiphospholipid syndrome (APS) is a systemic
autoimmune disorder characterized by arterial and/or venous thrombosis, fetal
death and recurrent miscarriages, and thrombocitopenia, along with elevated
titles of atiphospholipid antibodies (APA): lupic anticoagulant and/or cardiolipin.
Antiphospholipid syndrome was originally described in patients suffering from
systemic lupus erythematosus, and in the past 20 years the involvement of many
organs has been described. Cutaneous manifestations are frequent and in 41%
of patients they may represent the first manifestation of the syndrome.1
Livedo reticularis and cutaneous ulcerations are the most prevailing dermatological
manifestations. Treatment is based on anti-platelet aggregating or aticoagulant
drugs.2

The goal of this review is to make readers familiar
with historical, epidemiological and etiopathogenic aspects, clinical manifestations,
laboratorial diagnosis, differential diagnosis, treatment and prognosis of antiphospholipid
syndrome.

HISTORY

The first antiphospholipid antibody (APA), which
reacts with bovine heart antigens, was detected in patients with syphilis back
in 1906.3 It was later identified as cardiolipin, a mithocondrial
phospholipid.4

Conley and Hartmann were the first to describe,
in 1952, the presence of circulating anticoagulant in patients with systemic
lupus erythematosus (SLE).5

In 1963, Bowie et al.6 noted the relation
between systemic anticoagulants in patients with SLE and thromboembolic events.

Feinstein, Rapaport, in 19727 ssuggested
the name of "lupic anticoagulant" for this circulating anticoagulant, and Nilsson
et al.,8 in 1975, associated it to recurrent spontaneous abortions.

In 1983 Hughes9 described the association
between antiphospholipid antibodies and venous and arterial thrombosis.

In 1987 Harris et al.10 Proposed the
name antiphospholipid syndrome.

In the beginning of the 1990s, two groups discovered
that some anticardiolipin antibodies required the presence of a plasma phospholipid-bound
protein (antib2-glucoprotein I) to bind to cardiolipin.11,12

EPIDEMIOLOGY

Frequency

Frequency in the general population is unknown.
APAs can be found in 50% of systemic lupus erythematosus (SLE) patients, and
in percentages ranging from 1 to 5% of the healthy population, tending to occur
more often in the elderly. Recent studies suggest that the occurrence of antiphospholipid
syndrome in SLE patients is between 34% and 42%.13 In a study with
100 patients with venous thrombosis and no SLE history, 24% had anticardiolipin
antibody, and 4%, lupic anticoagulant.14

Mortality/morbidity

Antiphospholipid syndrome can contribute to a
increase in the frequency of strokes, especially in young individuals,15
as well as that of myocardial infarction. Valvular cardiac disease can be more
aggressive, requiring valve change.16 Recurrent lung embolus or thrombosis
may lead to pulmonary hypertension.15

Catastrophic antiphpospholipid syndrome is the
most serious manifestation, and is commonly fatal (mortality index of roughly
50%), and is characterized by infarctions in many organs within a period that
can vary from days to weeks.17,18

Even though spontaneous fetal loss usually occurs
in the second or third trimester of pregnancy, it can occur at any time.19

Race

There is no race predominance in APS.20

Gender

There is predominance in females, especially
in secondary APS. This is in accordance with the association between APS and
SLE and other connective tissue diseases, where there is predominance in females.20

Age

APS commonly occurs in young individuals and
middle-aged adults, although it can manifest in children and elderly. There
are reports of its occurrence in infants of less than eight months of age.20

An alteration occurs in the homeostasis of blood
coagulation. Mechanisms by which APAs interact with the coagulation cascade,
thereby producing clinical events, are speculative and have not been totally
elucidated yet. Presence of an endothelial lesion, associated to the presence
of an APA is a requirement for thrombotic complication.

Possible mechanisms by which APAs induce thrombotic
events:24,25

1. APAs can bind to platelet membrane phospholipids,
resulting in an increase of its adhesion and aggregation.

2. APAs can combine with endothelial cells membrane
phospholipids together with antib2-glucoprotein I
(b2-GP I) and induce activation of the endothelial
cell, thus leading to alteration of expression of adhesion molecules, citocin
secretion and prostaciclins metabolism, enhancing platelet adhesion and aggregation.

3. Lesion of the endothelial cell can also lead
to a decrease in endothelium-derived relaxing factor, thus enhancing vasospasm
and ischemia.

5. APAs can interfere in the interaction between
coagulation proteins C and S, consequently affecting the formation of the coagulation
control complex (activated protein C, protein S and factor V).

Possible mechanisms by which APAs can be produced:26-28

1. Autoimmunity.

2. APAS represent a response to internal membrane
antigens (e.g. phosphoserin), which are exposed by cells not cleared from circulation
due to overload or clearence system defect.

3. APAs may also be crossed reaction antibodies
induced by exogenous antigens of infeccious microorganisms (e.g. viral or bacterial).

CLASSIFICATION AND DIAGNOSTIC CRITERIA

Diagnosis depends on high clinical suspicion
and confirmation by laboratory findings. When arterial or venous thrombosis
occurs in patients who do not have obvious risk factors for thrombosis, or when
thrombotic events are recurrent, APS should be considered.29 However,
diagnosis can be difficult owing to a plethora of clinical manifestations and
laboratorial difficulties related to detection techniques and result standardization.
Moreover, antiphospholipid antibody levels can increase, diminish or occasionally
disappear in the course of the disease.30

Due to diagnostic difficulties, classification
criteria for the antiphospholipid syndrome have been formulated in a recent
consensus (Chart 2).29

Definite diagnosis of APS requires the presence
of at least one clinical and one laboratorial criterion, with no interval limits
between clinical event and laboratorial finding. Due to lack of worldwide agreement
to differentiate low from moderate or high anticardiolipin antibody levels,
three definitions are accepted: a) 15 to 20 phospholipid units separate low
from moderate anticardiolipin antibody levels; b) two or 2.5 times the average
level of anticardiolipin antibody; c) ninety-ninth percentile of anticardiolipin
levels of normal population.29

Antiphospholipid syndrome can be classified as
primary or secondary. The primary form occurs in the absence of related or base
diseases, being more common than the secondary,2 which is characterized
by the association with a large spectrum of ilnesses.21

In systemic lupus erythematosus (SLE), antiphospholipid
antibodies are present in over one third of patients, although not all of them
present the clinical syndrome.2 Clinical features and specific antibodies
are similar in both primary and secondary APS, and the clinical course of secondary
APS is independent on activity or severity of SLE.31

CLINICAL MANIFESTATIONS

The most common clinical manifestation of antiphospholipid
syndrome is thrombosis, which can affect arterial or venous vessels in any organ.
Venous thrombosis, particularly in the lower limbs - probably one of the most
common forms of venous thrombosis25 occurs in over 55% of APS patients.32
Other affected sites include renal, retinal and hepatic veins.25
Arterial thrombosis involves the brain in over 50% of the cases, causing transient
ischemic attacks (TIA) and strokes; approximately 90% of patients less than
50 years old with TIA are positive for antiphospholipid antibodies.33
Other sites of arterial thrombosis include heart, eyes, kidneys and peripheral
arteries.32 In APS, thrombosis episodes can occur in vascular beds
infrequently affected by other pro-thrombotic states.

Various obstetrical complications can be associated
to APS, including miscarriage (mainly in the end of the first trimester), fetal
death (in the second and third trimesters of pregnancy), pre-eclampsia, delayed
intrauterine growth and Hellp's syndrome.21 Fetal loss after 10 gestational
weeks is a feature of APS bearers, contrary to what is observed in general population,
in which miscarriages are more often within the first nine gestational weeks32
and associated to various causes.33

The spectrum of APS clinical manifestations is
large; it being able to affect various organs, being characterized by a predominance
of thrombotic microangiopathy or ischemia secondary to thromboembolic events34
(Chart 3).

Cutaneous manifestations

Cutaneous manifestations are generally explained
by vascular occlusion and represent a landmark for diagnosis and for the need
for extensive systemic investigation, since in 41% of patients suffering from
APS they constitute the first sign of the disease.2,35

Livedo reticularis (Figure 1)
and cutaneous ulcerations are the most frequent dermatological lesions,30
the former being characterized by purpuric and mottled vascular lesions, with
location, extension, infiltration and regularity of different patterns, and
which can be physiological or related to numerous conditions, such as SLE and
other immunological conditions, infectious diseases and cholesterol embolization.2
The association between APS and moderate to severe livedo reticularis is significant,2
and lesions are usually disseminated, infiltrated and have irregular pattern.30

Sneddon's syndrome, characterized by extensive
livedo reticularis and strokes,30,36,37 can be associated to APS,
and the state of hypercoagulability justifies these features;30 nevertheless,
the absence of antiphospholipid antibodies has been described.2

Cutaneous ulcerations normally appear in the
extremities, even though they can occur in other areas, leaving atrophic scars.30
There are four distinct types of ulcerations: 1. small, painful leg ulcerations,
of livedoid vasculitis; 2. large ulcerations similar to those of gangrenous
pioderma; 3. Delos type ulcerations; 4. periungueal ulcerations.38

Other cutaneous manifestations of APS are thrombophlebites,
more common in patients with primary APS when compared to controls,21
sharpned subungueal hemorrhages (multiple lesions in different fingers warn
the occurrence of thrombotic events) and a variety of lesions resembling vasculitis,
including purpuras, echimoses, painful nodules and erythematous maculae.30
Cutaneous gangrene has been reported in 19% of APS patients,2 and
disseminated superficial cutaneous necrosis occurs in 3% of the patients, being
the latter characterized by sudden onset painful purpuric lesions in the limbs,
head and buttocks.30

The association between Degos' disease (malignant
atrophic papulosis), anetodermia, progressive systemic sclerosis (PSS), discoid
lupus erythematosus (DLE) and T-cell lymphoma and antiphosholipid syndrome is
debated. Patients with apparent Degos' disease and positive for antiphospholipid
antibodies are speculated to have APS with livedoid vasculitic lesions, resembling
malignant atrophic papulosis. Anetodermia could develop due to dermal ischemia
and a consequent degeneration of elastic fibers. In PSS, elevated titles of
anticardiolipin antibody are found in 33% of patients. These antibodies are
proposed to modulate platelet function, resulting in tissue fibrosis and vascular
injury. Rarely, DLE lesions can be associated with APS, with no clinical or
laboratorial evidence of SLE. In T-cell lymphoma, neoplastic clones are suggested
to be able to induce B-cell proliferation with the production of antiphospholipid
antibodies.2

LABORATORIAL DIAGNOSIS

Antiphospholipid antibodies

Antiphospholipid antibodies form a familily of
autoantibodies that exhibit a great spectrum of specific targets, all of them
recognizing various combinations of phospholipids, phospholipid-bound plasmatic
proteins or both.34 They can be IgG, and/or IgM, or, less often,
IgA.39 Even though these antibodies have not yet been conclusively
evidenced as a cause of thrombosis and abortions, they are useful laboratorial
markers of APS.40 The most common antiphospholipid antibodies subgroups
are lupic anticoagulant antibody, anticardiolipin antibody and antib2-glucoprotein
I antibody. Recent works have described antibodies such as antiprothrombin;
however, furher work is still needed for the establishment of its clinical relevance.41

Anticardiolipin antibodies are currently detected
by an ELISA-type standardized test, which measures immunological reactivity
to phospholipids or to b2-glucoprotein phospholipids-bound
proteins.42 Results are expressed quantitatively:33

a. weakly positive if IgG varies between 5 and
15 GPL (IgG phospholipid) or if IgM is lower than 6 MPL (IgM phospholipid);

b. moderately positive if IgG varies between
15 and 80 GPL, and IgM between 6 and 50 MPL; and

c. strongly positive if IgG is over 80 GPL and
IgM ove 50 MPL.

High IgG levels are seemingly more clinically
relevant in terms of predicting the occurrence of thromboses, thrombocitopenia
and recurrent miscarriages. Many cases of low or moderate levels of anticardiolipin
antibodies have proven to be transient, able to result in occasional interoccurring
infections. This is why it is important to repeat the test after six or eight
weeks after an initial positive result. Persistence of anticardiolipin antibody
in he serum is a necessary criterion for establishing APS.2

Antib2-glucoprotein
antibodies are also detected by immunoassay technique (ELISA).43,44
Presence of antib2-glucoprotein IgG has a high specificity
for APS; however, it has low sensitivity, thus its detection should be associated
to that of antiardiolipin antibodies.29 Although its positivity is
not currently included in the criteria for APS, antib2-glucoprotein
antibodies are also related to thromboses and other APS manifestations.34

Lupic anticoagulant antibodies are directed against
phospholipid-bound proteins, such as b2-glucoprotein
I or prothrombin, and are detected by tests that assess phospholipid-dependent
coagulation.45 Due to their heterogenous nature, performing more
than one assay becomes necessary for a correct diagnosis. There are different
methods to detect a lengthening of clotting time (Chart 4).34
The most frequently used are aPTT (activated partial thromboplastin time), KCT
(Kaolin clotting time) and dRVVT (dilute Russel's Viper Venom Time). aPTT was
previously used as a screening test for lupic anticoagulant antibody,2
but its sensitivity in APS patients is approximately 30% to 40%. Therefore,
many patients with APS have a normal aPTT. KCT is a good screening test for
lupic anticoagulant, though the technique is difficult and has complicating
factors. dRVVT (based on snake poison) is the most sensitive,29 thus
being the prefered method for the detection of lupic anticoagulant antibody.
A more complete screening demands a combination of all of these tests.2

In spite
of the frequent concordance between lupic anticoagulant antibody and anticardiolipin
or antib2-glucoprotein, these antibodies are not
identical. Some lupic anticoagulant antibodies react with phospholipids other
than cardiolipin and with other proteins besides antib2-glucoprotein,
whereas some anticardiolipins and antib2-glucoprotein
antibody do not have activity against lupic anticoagulant.34 Cooccurrence
of both anticardiolipin and lupic anticoagulant antibodies in a same patient
ranges between 50% and 75%.21 Several antipospholipid antibodies
assays should be used for laboratorial diagnosis of APS, since the patient can
be negative according to one test and positive according to another.34

Generally, lupic anticoagulant antibodies are
more specific for APS, albeit anticardiolipin antibodies are more sensitive.
APS specificity of anticardiolipin antibody increases with title increase and
is higher for IgG than for the IgM isotype.34

In studies of the association between the presence
of antiphospholipid antibodies and the risk for thrombosis, lupic anticoagulant
was concluded to be a clear risk factor for thrombosis, regardeless of type
or site of affection, presence of SLE or of the methods used for detection.
Conversely, anticardiolipin antibody and antib2-glucoprotein
antibody are possible risk factors for thrombosis in a few selected situations.
Measurement of antiprothrombin antibodies, on the other hand, have not been,
to date, helpful in the definition of thrombosis risk, due to the lack of data
proving their clinical association with APS.39

Histopathology

Skin biopsy is usually necessary for a differential
diagnosis. Absence of vasculitis and the finding of non-inflammatory thrombosis
of small dermal and hipodermal arteries and veins are the characteristic cutaneous
lesions of antiphospholipid syndrome.34

DIFFERENTIAL DIAGNOSIS

Differential diagnosis of the antiphospholipid
syndrome should be made with patients presenting thromboembolic disorders, infections,
vasculidites and increased KPTT (Kaolim partial thromboplastin time).29

Thromboembolic Disorder

Antiphospholipid syndrome is one of the many
disorders that present a hypercoagulable state, in which thromboembolic phenomena
can happen in both arterial and venous territory.46 Differential
diagnosis should be made with diseases and predisposing factors for thromboembolism,
such as clotting factors deffects, clot lysis, metabolic defects, platelet alterations,
stasis (immobilization, surgery), hyperviscosity, vessel wall defect, use of
oral contraceptives, estrogen therapy, pregnancy, puerperium, neoplasia, diabetes,
hypertension, cigarrette smoking, hyperlipidemia.34

Contrary to other predisposing diseases, which
can be identified by means of laboratory exams, APS can display as single alteration
the presence of antiphospholipid antibodies. Diagnosis may not be suspected
in patients that present symptoms of slow and gradual evolution, potentially
leading to idle ischemia and progressive functional loss of an organ.34

Infections

When high levels of antiphospholipid antibodies
are detected, the possibility of an infectious cause should be considered. These
antibodies are frequently seen in patients with syphilis, Lyme's disease, HIV-1,
Micoplasma infections, malaria and viral infections such as hepatites
C, adenovirus, rubella, varicella and mumps.29 Diagnosis will be
made clear with specific tests for the suspected infection.

Vasculiditis

The majority of APS patients has altered clotting
screening tests, arterial or venous thrombosis and recurrent abortions. When
vascular occlusion occurs in the presence of a known autoimmune disease, e.g.
SLE, the possibility of vasculiditis should be considered.47 Particularly
in patients with catastrophic APS, multisystem vascular occlusion can simulate
a disseminated vasculiditis, such as thrombotic thrombocitopenic purpura (TTP)
and disseminated intravascular coagulation (DIVC).48 In TTP, the
finding of microangiopathic hemolytic anemia (squizocytes) associated with fever,
neural and renal alterations, albeit with normal coagulation tests is common.
On the other hand, in DIVC, the patient usually has a base disease, which evolves
with complex coagulopathy and with formation of fibrin degradation products
and increased KPTT.

Increased KPTT

Increased KPTT as an isolated laboratory finding
can occur in acquired or hereditary deficiencies of clotting factors VIII, IX,
XI and XII. It can also occur secondarily to the presence of an inhibiting factor,
which can be a specific factor itself (e.g. an antibody against factor VIII)
or a non-specific one (e.g. heparin or lupic anticoagulant). For this reason,
KPTT is considered as a good screening test to assess inhibitors such as lupic
anticoagulant.49 In order to differentiate between deficiency of
a factor and presence of an inhibitor, normal plasma should be used. In APA,
there is a failure in the correction of KPTT even after the infusion of normal
plasma. The finding of antiphospholipid antibodies help to confirm the diagnosis.
In the presence of specific inhibiting factors, such as antifactor VIII antibody,
KPTT is increased due to a reduction of the clotting factor's levels. After
mixing normal plasma in the proportion of 1:1, an immediate correction of its
values occurs; however, KPTT might increase again within one or two hours under
a temperature of 37ºC.29 Inhibitory effects of fibrin degradation
products in DIVC can also prolong KPTT. Moreover, depending on the reactant
system used, heparin effects (therapeutic or contamination) can also be detected
through KPTT prolonging, even in concentrations which are considered low, like
0,05U/ml.29

In cutaneous gangrene and necrosis which occur
in APS, antiphospholipid antibodies can be associated with other pathogenic
circulating factors, such as crioglobulins, hepatitis antibodies or antiendothelial
antibodies.2

Patients with SLA and antilupic antibodies may
present ulcerations that leave scars with china-like atrophic centers when involute,
mimmicking Degos' disease. This latter syndrome is a rare entity, with leality
of 50%, and in which antiphospolipid antibodies are negative.2

TREATMENT

Primary profilaxis, prevention of recurrent thrombosis,
treatment of acute thrombosis and handling during pregnancy should all be considered
for the treatment of APS.

Profilaxis

Patients who are positive for antibodies but
have no history of thrombosis are not candidates for profilatic treatment with
drugs.2 Nevertheless, risk factors for thrombosis, e.g. hypertension,
smoking, hypercholesterolemia, contraceptive use and prolonged immobilization
should be eliminated.50

Profilatic use of aspirin in low doses is useful
for prevention of thrombosis in women with recurrent miscarriages, but it does
not prevent deep venous thrombosis in men with APS.29,34,50 In SLE
and secondary APS, hydroxicloroquine has shown protecting effect against thromboses,
not to mention reduction of cholesterol levels and glicemia.2,29,34

Patients who undergo surgery and need to be immobilized
for long periods of time require profilatic heparinization, and in APS sometimes
doses should be higher than usual, namely, 25,000 to 40,000U/day, due to resistance
to anticoagulants effects.2

Treatment of obstetrical complications

Presence of antiphospholipid antibodies increases
risk of miscarriages during the fetal period (over 10 gestational weeks) and
of premature labor due to uteroplacentary failure.2,34 Treatment
has evolved, thus decreasing the number of these complications (Chart
5).

Use of prednisone, at the daily dose of 40mg,
has decreased incidence of spontaneous abortion, but increased the number of
preterm labors and maternal morbidity,32,51,52 including diabetes,
hypertension and sepsis.32 Although intravenous immunoglobulins can
be used for the treatment of a few autoimmune diseases during pregnancy, randomized
studies have not demonstrated benefit in comparison to heparin treatment in
APS.34,51,52

Many prospective studies have demonstrated that
treatment with a combination of heparin and low-dose aspirin are more effective
in preventing spontaneous abortions in patients with APS than aspirin alone,2,29,32,34,40,51,52
hence, this should be initiated as soon as pregnancy is confirmed.34,40
Aspirin dose should be of 81mg/day; however, heparin dosing is still a controversial
issue.2,29,32,34,51,52 Some authors recommend doses of 5,000 SC every
12 hours, in the absence of a history of previous thromboses,32,52
while others recommend doses which vary according to pregnancy stage and previous
history of thrombosis.32,51

Non-fractioned heparin can be replaced by low
molecular weight heparin, with the advantage of daily administration, in addition
to reducing the risks of low platelet counts and osteoporosis induced by non-fractioned
heparin.29,32,34,40 The low molecular weight heparins used in pregnancy
are enoxaparin 40mg/day and dalteparin 5,000U/day.29

Incidental finding of antiphospholipid antibodies
during pregnancy with no previous clinical history of its complications does
not require treatment.29

Patients using warfarin for previous thrombosis
should have their treatments substituted with heparin in the course of pregnancy,
due to the latter's teratogenic effects.2,32

Catastrophic antiphospholipid syndrome

This rare manifestation of APS, characterized
by generalized vascular occlusion, often resulting in death, might not respond
to isolated anticoagulant therapy. Treatment is made with a combination of anticoagulation,
steroids, and plasmapheresis or intravenous immunoglobulin.2,29,32,34,50
The use of fibrinolytic agents has no proven benefit.

Treatment after primary thrombotic event

There is no evidence that acute treatment of
thrombosis secondary to APS should be any different from treatment of acute
thrombosis due to other causes.20 Initial therapy is made with non-fractioned
or low molecular weight heparin, followed by warfarin.32,51 Since
patients with APS and thrombosis are at high risk for recurrent thromboembolism
episodes, prolonged, perhaps life-long oral anticoagulation therapy is a guarantee
for the prevention of new episodes.29 The most widely used oral anticoagulant
is warfarin. Studies show still variable resultes concerning intensity of anticoagulant
treatment.32,40,50,51 Whereas some indicate a lower risk for new
episodes of thrombosis with an intensive warfarin treatment, maitaining INR
> 3,2,29,53,54 other studies, including a prospective one,55
show that INR can be maintained between 2 and 3 in control, with recurrence
indices similar to patients with INR > 3, albeit with lower bleeding risk.34,55,56

Cutaneous manifestations in general respond to
the treatment of base disease. There are studies which report cure of chronic
ulcerations caused by livedoid vasculiditis after the use of fibrinolytic agents.2

EVOLUTION, PROGNOSIS AND COMPLICATIONS

Clinical manifestations of APS are quite heterogenous,
which determines a highly variable evolution.57,58

Even though the association between clinical
manifestations and presence of antiphospholipid antibody is more evident in
primary APS, there is no difference in evolution of primary or secondary forms.34

There is little consistent data in the literature
concerning prognosis and clinical evolution of patients. A few recent studies
suggest three forms of evolution:59

2. recurrent episodes: APS frequently occurs
with recurrence of its clinical manifestations, mainly thrombotic events.57,60,61
Anticardiolipin antibodies titles greater than 40, associated with a previous
thrombosis episode, are independent risk factors for a new thrombosis episode.
Patients with SLE and who are positive for anticardiolipin antibodies have a
higher predisposition to recurrent thrombotic events. Average time between the
first and the second event is three years. The severity of the initial clinical
manifestation and the presence of antib2-GPI antibody
in the first episode of the disease suggest a worse prognosis, since average
time for the second event is reduced to less than 12 months;57,62

3. catastrophic antiphospholipid syndrome (CAS)
or Asherson's syndrome: is an uncommon variant of APS, predominantly characterized
by small vessel obstructive disease, affecting at least three different organs
in a period varying from days to weeks. It manifests clinically as three distinct
forms:48

a. einitial event of APS;

b. primary evolution of APS: most common form;

c. secondary evolution of APS (commonly associated
with SLE).

The reason why some patients develop thromboembolic
events in large vessels and others in small vessels is still unknown. Notwithstanding
the fact that 45% of the patients do not have a well defined triggering factor,
it is postulated that infections, trauma, coagulopathies, use of medication,
neoplasias, pregnancy and acutization of SLE might be involved as triggers of
this syndrome.48

The kidney is the most affected organ, followed
by the lung, CNS, heart and skin (55% to 66%). The most commom dermatological
manifestations are livedo reticularis, skin necrosis and purpura.34

The mortality rate is 50% and death is due to
multiple organ dysfunction.34,48,59

Prognosis of patients suffering from APS is quite
variable and depends on different factors:

1. severity of initial clinical manifestation:
the kind of initial clinical manifestatin affects both the frequency and type
of a subsequent event. If the clinical picture is associated with high anticardiolipin
antibody titles (over 40); if there are two associated clinical manifestation
(e.g. livedo reticularis and venous thrombosis) or hemolytic anemia as the initial
manifestation, prognosis is worse;57,59

2. previous disease history: A previous
thrombotic episode increases the probability of a new event;60

3. high antibody levels: presence of antib2-GPI
in the initial picture increases the probability of complications in over 50%;

4. proper therapy: the use of anticoagulants
decreases the probability of serious events by about 78 to 91%;34,57,60

The Antiphospholipid Syndrome is a multisystem
disorder associated with a variety of circulating antibodies, the targets of
which are different phospholipid complexes. The main clinical manifestations
are fetal loss and arterial and/or venous thrombotic complications, which may
manifest as cutaneous lesions. It is important for the dermatologist to recognize
cutaneous signs associated to this syndrome, thus collaborating for its early
diagnosis and treatment. q